1. Field of the Invention
This invention generally relates to novel pharmaceutical compositions for oral administration. This invention relates in particular to such compositions in the form of floating bilayer controlled release system for delivery of one or more active agents.
This invention relates more particularly to immediate delivery of a first active agent followed by continuous controlled delivery of a second agent, which may be same or different from the first active agent, while the system or dosage form floats in the fluid of the environment (e.g., the stomach), thereby being retained in the environment of use for an extended period of time.
2. Description of the Prior Art
Various proposals have been made to achieve controlled release pharmaceutical compositions to slow down the release rate of a drug from preparations so that therapeutically active concentrations are maintained in the body for longer time. In recent years, there have been numerous developments in polymeric carriers and controlled release systems such as films with the drug in a polymer matrix, monolithic devices, reservoir device, microparticles, microspheres or nanoparticles in the form of reservoir and matrix devices, osmotic pumps, pH dependant coatings, soluble polymers with covalently attached ‘pendant’ drug molecules.
Oral route is the most preferred route of administration for various types of active agents however few active agents exhibit a “small absorption window” in gastrointestinal tract i.e. they are more effectively absorbed only from stomach, duodenum, and initial portion of small intestine. (e.g. methyl dopa, captopril) Hence, in case of such active agents to achieve maximum absorption, it is mandatory to retain these drugs in stomach for extended period of time.
Some active agents are intended for exerting a medical action at gastric level e.g. antibiotics like ofloxacin, ciprofloxacin in the treatment of H. pylori infection, antacids, proton pump inhibitors and H2 receptor antagonists. In order to achieve maximum therapeutic efficacy, it is beneficial to maintain such drugs in close proximity to gastric mucosa.
There also exists a requirement of therapeutic cases wherein administration (as acute/symptomatic treatment) of a first therapeutically effective dose of an active agent is required whereas in following steps, slow administration of maintenance dose of the same or different drug is necessary. These types of therapeutic needs result in complicated dosage regimen that are not always correctly adhered to by the patients especially the outpatients. Non compliance with dosage regimen is directly proportional to complexity and no. of daily doses.
The major concern with antibiotic therapy is development of resistance by microorganisms. The variation in the antibiotic drug concentrations in the body fluid after conventional drug therapy leads to development of resistance by microorganisms. Many a times this problem is further aggravated due to patient non-compliance due to missed doses.
Fluoroquinolones are one of the most widely used in the management of infectious diseases. Their potent and broad spectrum of activity, efficacy and relative safety make them useful for both community acquired and nosocomial infections. However, inappropriate prescribing and missed posology can lead to antimicrobial resistance.
The candidates representing fluoroquinolone class are ciprofloxacin, ofloxacin, pefloxacin, grepafloxacin, enoxacin, amifioxacin, fleroxacin, temafloxacin, lomefloxacin, norfloxacin, sparfloxacin, levofloxacin, gatifloxacin and moxifloxacin. Ciprofloxacin and ofloxacin have exhibited wide spectrum of antimicrobial activity.
The present invention will be further elaborated with exemplifications with ciprofloxacin and ofloxacin those being the representative candidates of fluoroquinolone group but the scope of the invention is not limitative thereof.
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1, 4-drhydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid. It is a faintly yellowish to light yellow crystalline substance. Ciprofloxacin differs from other quinolones in that it has a fluorine atom at the 6-position, a piperazine moiety at the 7-position, and a cyclopropyl ring at the 1-position. The recommended adult dosage 500-mg every 12 hours. The usual duration of treatment is 7–14 days.
An important factor affecting the absorption of orally administered drug through gastrointestinal tract is transit time in gastrointestinal tract. Ciprofloxacin is absorbed only from the stomach to the jejunum. Hence to achieve maximum efficacy it would be beneficial if the drug is retained in stomach for extended period of time. This problem can be overcome by developing a system that is retained in stomach for prolonged time and can release active agent in a controlled manner.
Another widely used fluororquinolone candidate, ofloxacin is the racemate, (±)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido [1,2,3-de]-1,4-benzo-xazine-6-carboxylic acid. Ofloxacin is an off-white to pale yellow crystalline powder. The molecule exists as a zwitterion at the pH conditions in the small intestine. The relative solubility characteristics of ofloxacin at room temperature indicate that ofloxacin is considered to be soluble in aqueous solutions with pH between 2 and 5. It is sparingly to slightly soluble in aqueous solutions with pH 7 and freely soluble in aqueous solutions with pH above 9. The usual dose of ofloxacin is 200 mg to 400 mg every 12 hours and the usual duration of treatment is 7–10 days. Considering the maximum solubility of drug, it would be more beneficial to retain the drug in stomach for prolonged duration so as to achieve maximum absorption.
As described above and exemplified with the two leading fluoroquinolone derivatives, the efficacy and patient compliance of the fluoroquinolones and similar drugs can be improved by retaining the compositions in stomach for longer time. To facilitate their longer duration of treatments and to avoid variation in drug concentrations in the body (which occurs with conventional therapy) it is further desirable to extend the release of drug that would lead to better patient compliance and success of therapy.
Thus, in the view of the above discussion it can be concluded that to achieve maximum efficacy of the fluoroquinolone derivatives it is desirable to retain the active agents in stomach and acquire uniform continuous release of the same in a controlled manner. It is also desirable to avoid the initial lag time in the release of antibiotic from controlled release composition hence the pharmaceutical composition of the present invention is designed to have an initial loading dose as an immediate release form.
The concept of bilayer tablet is well known in the art which is generally employed for various purposes such as stabilization (U.S. Pat. No. 6,287,600), taste masking (U.S. Pat. No. 5,690,959) or delivering two drugs having synergistic effects (U.S. Pat. No. 6,319,519). Bastin described use of bilayer tablet for administration of drugs prone to abuse where the drug layer and gelling layer are separate and the concentration of gelling agent is such that it doesn't retard release of active agent but facilitates drug release similar to that of conventional tablet. Blume (U.S. Pat. No. 6,372,252) discloses guaifenesin sustained release bilayer tablet offering bioavailability of drug for 12 hours where first portion is of immediate release and second is for controlled release. The release is not site specific.
Several literatures describe buoyant dosage forms which improve gastric residence time. Most of the patents disclose monolithic systems (U.S. Pat. Nos. 4,126,672 and 4,167,558). U.S. Pat. Nos. 4,814,178 and 4,814,179 describe non-complexed sustained release floating tablets including hydrocolloid gelling agent, oil, selected therapeutic agent, water and have multitudes of air holes with density less than 1. These systems are not restricted to floating in gastric fluid. U.S. Pat. No. 4,140,755 discloses two layered buoyant tablet containing antacid where one layer is formulated to immediately release the active and other to obtain density lower than gastric fluid and provide controlled release of drug. Franz (U.S. Pat. No. 5,232,704) discloses sustained release bilayer formulation where one layer is drug release layer and other is a floating layer which releases all the drug over a extended period in stomach. Conte et al (U.S. Pat. No. 5,681,583) disclosed pharmaceutical multilayered tablet which exhibited high volume increase in contact with biological fluid, increasing volume of tablet and retaining the dosage form in stomach. Dennis (U.S. Pat. No. 5,169,638) described buoyant controlled release powder formulation comprising basic active agent, salt of alginic acid and hydrocarbon gelling agent. Alza corporation (U.S. Pat. Nos. 4,036,228, 4,847,093, 4,344,929) describe osmotic device containing gas generating agent and releasing drug as a effervescent generated fine dispersion over osmotic gradient. U.S. Pat. No. 4,777,033 discloses oral compositions containing sodium bicarbonate as gas generating agent along with hydrocolloid polymer which offers buoyancy to the system and releasing drug in a controlled manner but not specific to stomach.
All the above systems describe either bilayer tablets or gastro-retentive compositions or combined bilayer gastro-retentive formulation which are either intended for immediate release, or only for controlled delivery of drugs which pose problems of bioavailibility fluctuations. To overcome these insufficiencies, the inventors of the present invention have come out with a novel pharmaceutical composition of floating bilayer system wherein the first layer is designed to release active agent immediately avoiding lag time in the therapy and the matrix forming second layer that releases drug in a controlled manner while the system floats in gastric environment.
The present invention relates to a controlled release fluoroquinolone formulation for oral administration and methods of its manufacture. In particular, it relates to a controlled release fluoroquinolone formulation which maintains a therapeutically effective blood concentration of fluoroquinolone with once a day administration. The present invention further relates to a modified release bi-layer fluoroquinolone tablet which demonstrates a maximum serum concentration equivalent to an immediate release tablet yet maintains a therapeutically effective blood concentration with once a day administration.